Structural features and binding free energies for non-covalent inhibitors interacting with immunoproteasome by molecular modeling and dynamics simulations

Immunoproteasome subunit LMP7 is an important target for development of various novel therapeutic agents. In the present study, we examined the detailed binding structures and free energies for a promising series of non-covalent inhibitors interacting with LMP7 by carrying out homology modeling, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decompositions. The obtained protein-inhibitor binding structures and energetic results have revealed some interesting structural features of the non-covalent inhibitors binding with the LMP7 subunit and valuable insights into the factors affecting the activity of these non-covalent inhibitors. Based on the MD-simulated protein-ligand binding structures, the calculated binding free energies are in good agreement with the experimental activity data for all of the inhibitors examined, which suggests that the computational protocol and the obtained structural insights are reasonable. The obtained computational insights, along with the binding free energy calculation protocol tested in this study, are expected to be valuable for rational design of new, more potent non-covalent inhibitors of LMP7.